The goals of this proposal are to expolore the relationship of the HPT axis and treatment response in Major Depressive Disorder (MDD). We will systematically examine the value of concomitant thyroid hormone with sertraline, a selective serotonin reuptake inhibitor (SSRI) antidepressant medication in the treatment of MDD. Two overlapping populations of MDD patients will be the focus of this study: (1) those with peripheral evidence of hypothalamic pituitary thyroid (HPT) axis abnormalities, and (2) those who did not respond to previous adequate treatment with an SSRI. This proposal is primarily a study of treatment efficacy with related implications for the underlying pathophysiology of MDD, in a well defined group of patients with MDD. We propose to programmatically develop a large study population of patients with MDD classified with respect to HPT abnormalities and response to SSR antidepressant treatment, both retrospectively and prospectively. Such a cohort will allow the examination of the role of the HPT axis in the pathophysiology and heterogeneity of MDD.